CS243588B1 - Method of 2(3-fluorophenylthio)-5-chlorphenyl)acetyc acid's new thiomorpholide's preparation - Google Patents

Abstract

The solution lies in the field of drug synthesis. His subject] e way of preparing a new one [2- (3-fluoro-phenylthio) -5-chloro-phenyl] -acetic acid thiomorpholide (I) which is an intermediate production of psychotropic and neurotropic drugs. The method of preparation lies in reacting 2- (3-fluorophenylthio) -5-chloroacetophenone (II) with sulfur and boiling morpholine, used in 200 to 300% excess.

Description

(54) Process for the preparation of the new [2- (3-fluorophenylthio) -5-chlorophenyl] acetic acid thiomorpholide 2

The solution falls within the field of drug synthesis. It provides a process for the preparation of the novel [2- (3-fluorophenylthio) -5-chlorophenyl] acetic acid thiomorpholide (I), which is an intermediate in the manufacture of psychotropic and neurotropic drugs. The process consists in reacting 2- (3-fluorophenylthio) -5-chloroacetophenone (II) with sulfur and boiling morpholine used in a 200 to 300% excess.

AND

The present invention relates to a process for the preparation of the novel (2- (3-fluorophenylthio) -5-chlorophenyl) acetic acid thiomorpholide of the formula I

The compound of formula I is an intermediate in the manufacture of psychotropic and neurotrophic drugs and is therefore technically significant. It has not yet been described in the literature.

The method of preparation of the compound I according to the invention consists in applying the Willgerodt reaction in the Kindler modification (Kindler K., Justus Liebigs Ann. Chem. 431, 193, 222, 1923) to 2- (3-fluorophenylthio) -5-chloroacetophenone of formula II

by reacting the compound of formula II with sulfur and excess morpholine at the boiling point of the reaction mixture. Morpholine is used in a 200 to 300% excess and is operated at a bath temperature of 150 ° C. After completion of the reaction, the reaction mixture was dissolved in more organic solvent, the insoluble matter was removed by filtration, the solution was washed with water and dilute hydrochloric acid to remove excess morpholine, evaporated and the residue crystallized from ethanol. Ethanol is used as the organic solvent and after evaporation of the ether, or directly benzene or chloroform. The yield of the modification used is 58 to 75%. The product is a crystalline solid melting at 111-112 ° C. His identity was assured by analysis and spectra. The starting material of formula (II) has not yet been described in the literature and its preparation is therefore given in Example 1. The following examples are intended to describe the details of the process for the preparation of the compound of formula I according to the invention and to illustrate the possibilities of the invention. It is not intended to limit the scope of the invention to the cases set forth or exhaustively describe all possibilities.

Example 1

A mixture of 40.9 g of 2- (3-fluorophenylthio) -5-chloroacetophenone, 9.4 g of sulfur and 43 g of morpholine was first heated under stirring at 120-140 ° C for 1 hour and then heated under reflux for 10 hours. at a bath temperature of 140-160 ° C. After cooling, the mixture is dissolved in 250 ml of ethanol, filtered with charcoal and the filtrate is evaporated under reduced pressure. The residue (68.2 g) was dissolved in 1100 ml of ether and the solution was washed successively several times with 2% sodium hydroxide solution, water, dilute hydrochloric acid and water again. Dry over sodium sulfate, filter through a pad of silica gel and charcoal and evaporate the yellow filtrate. The residue (43.2 g) was crystallized from 60 ml of boiling ethanol; 32.4 g (58%) of product I melting at 99 DEG-108 DEG C. are obtained, which is sufficiently pure for further processing. By further crystallization from ethanol, a completely pure material melting at 111-112 ° C can be prepared.

The starting 2- (3-fluorophenylthio) -5-chloroacetophenone (II) used is a substance which has not been described in the literature. It can be obtained from the starting materials described as follows:

To a mixture of 32.5 g of 2-fluorothiophenol (Rajšner M., Protiva M., Collect. Czech. Chem. Commun. 32, 2021, 1967) and 45 g 2,5-dichloroacetophenone (Rajšner M. et al., Collect. Chem. Commun. 43, 1276 (1978), 1.1 g of powdered copper and 56 g of potassium carbonate are added. The mixture is heated with stirring in a bath of 140-160 ° C for 3.5 h. After cooling to 50 ° C, the mixture is extracted with 100 ml of benzene, the insolubles are filtered off with suction and washed with benzene. Evaporation of the benzene extract gave 68.1 g of a residue which was dissolved in 300 ml of hot ethanol. The solution is filtered with charcoal, the filtrate is concentrated under reduced pressure to a total volume of 120 ml and left to crystallize at room temperature for 12 h. 38.1 g (54%) of compound II melting at 48.5 to 52 are obtained. ° C and clean enough for further processing. Recrystallization from ethanol gave the analytical product, mp 53-54 ° C. Example 2

A mixture of 64.5 g of 2- (3-fluorophenylthio) -5-chloroacetophenone (II), 14.8 g of sulfur and 68 g of morpholine was stirred and heated under reflux for 1 hour in a 120 ° C bath and then for 9 hours in a bath. temperature 150 ° C. After partial cooling, the reaction mixture is diluted with 500 ml of benzene and washed successively with 400 ml of water, 400 ml of 1.5 M HCl and again with water. Dry with potassium carbonate and filter with 5 g of activated carbon through a layer of 50 g of silica gel. Wash with ether. The filtrate was evaporated under reduced pressure, the residue (77 g) was dissolved in 95 ml of hot ethanol and left to crystallize; 63 g (74%), mp 102-106 ° C. Example 3

A mixture of 175 g of 2- (3-fluorophenylthio) -5-chloroacetophenone (II), 40.2 g of sulfur and 185 g of morpholine was heated under reflux for 1 hour in a bath at 120 ° C and then stirred for 10 hours in a bath. Mp 150-155 ° C. After partial cooling, it is diluted with 1.5 L of chloroform and washed successively with 1000 ml of water, twice with 750 ml of 1.5 M HCl and again with 1000 ml of water. Dry 85 g of potassium carbonate and, after addition of 15 g of activated carbon, filter through a layer of 135 g of silica gel. The filtrate was evaporated under reduced pressure and the residue (235 g) was crystallized from 275 ml of ethanol; 177 g (74%) of 1.1.1. Mp 100-105 ° C.

Claims (1)

Subject Process for the preparation of the novel [2- (3-fluorophenylthio) -5-chlorophenyl] acetic acid thiomorpholide of the formula I CHCSr / ~ O lil OF THE INVENTION characterized in that 2- (3-fluorophenylthio) -5-chloroacetophenone of formula II is folin used in an excess of 200 to 300%.